Russell Marker and the Mexican Steroid

Hormone Industry
International Historic Chemical Landmark
Dedicated October 1, 1999, at Pennsylvania State Universitys Pond Laboratory in
University Park, Pennsylvania, USA, and December 2, 1999, at Syntex Laboratory in
Mexico City, Mexico.

Steroid chemists often refer to the 1930s as the Decade of the Sex Hormones, when the
molecular structures of certain sex hormones were determined and first introduced to
medical practice as drugs. Russell Marker achieved the first practical synthesis of the
pregnancy hormone, progesterone, by what now is known as the "Marker Degradation."
Produced from starting material in a species of Mexican yam, Markers progesterone
eventually became the preferred precursor in the industrial preparation of the anti-
inflammatory drug cortisone. Important research on sex hormones continued in Mexico,
leading to the synthesis of the first useful oral contraceptive in 1951.

The Marker Degradation and Creation of the Mexican Steroid Hormone Industry
1938-1945 commemorative booklet produced by the National Historic Chemical
Landmarks program of the American Chemical Society in 1999 (PDF).

"Marker Degradation" and the Decade of the Sex Hormones

The Decade of the Sex Hormones that's how steroid chemists often refer to the
1930s, when the molecular structures of the male hormone, testosterone, the female
hormones, estrone and estradiol, and the pregnancy hormone, progesterone, were
determined and first introduced to medical practice as drugs.

Much attention was focused on progesterone because of its value in treating various
menstrual disorders and preventing certain types of miscarriages; however, its high cost
severely restricted its use. The cost of progesterone and other important steroids fell
drastically in the 1940s with the creation of the Mexican steroid industry. According to
Carl Djerassi ("The Father of the Pill"), the "Mexican connection stemmed from the
work of one gutsy individualist, Russell E. Marker," about whom more stories have
been told, "many of them apocryphal than about almost any other chemist."

In 1938, Marker, then a chemistry professor at The Pennsylvania State College (now,
University), proposed a remarkable new molecular structure for sarsasapogenin, a plant
steroid isolated from sarsaparilla. In Marker's structure, the side chain part of the
molecule (the red part of the formula at right) is chemically reactive because two
oxygen atoms are connected to the same carbon atom. Earlier workers had supposedly
confirmed "beyond any doubt" a sarsasapogenin structure in which the side chain was
chemically inert. Using this reactivity, Marker invented a chemical reaction sequence
that removed most of the atoms in the side chain. What remained duplicated the side
chain of progesterone. (Chemists call such processes "degradations.") Subsequent
chemical modification of the steroid ring system then yielded progesterone itself.
Because of the high cost of sarsasapogenin and the major expense involved in these
final manipulations, Marker began a search for a plant steroid of the sapogenin class
with a ring structure more like progesterone. He found it in Beth root, a plant of the lily
family, which already was being used in a patent medicine called "Lydia Pinkham's
Compound." Japanese chemists previously had isolated this steroid from a yam of the
Dioscorea family and named it diosgenin. As anticipated, when diosgenin was
subjected to the "Marker Degradation," progesterone was obtained. However, neither
Beth root nor the Japanese Dioscorea was an economical source of diosgenin.

In his search for a better diosgenin source, Marker recruited several botanists and
launched extensive plant-collection trips mainly in the southwestern United States.
More than 400 species were examined and a dozen new sapogenins were identified and
characterized. Then, in November 1941, while in Texas, Marker was paging through a
botany text when he saw the picture of a Dioscorea that grew in the Mexican state of
Veracruz near Orizaba. The root of this plant, called cabeza de negro by the natives,
was said to weigh up to 100 kilos.

What are Steroids?

Steroids are fat-soluble compounds with complex molecular structures that occur in
almost all living organisms. They always have a ring system of carbon atoms with three
6-membered rings and one 5-membered ring connected to each other. The 5-membered
ring can be attached to a side chain of carbon atoms that may be quite long (e.g.,
cholesterol and diosgenin), short (e.g., progesterone), or even nonexistent (e.g.,
testosterone, estrone, and estradiol).

THE MARKER DEGRADATION

Marker Discovers Mexican Dioscorea

When Marker went to Mexico City in January 1942, the U.S. Embassy advised him to
leave immediately because of widespread anti-American sentiment fueled by World
War II. Instead, Marker took a bus to Orizaba, changed to the local bus to Cordoba, and,
on the way, recognized the stream described in the botany text. By the stream, he found
a country store owned by Alberto Moreno, a native Mexican who did not speak English.
Despite the language barrier, Moreno was enlisted to find some cabeza de negro.
Although Marker had no plant-collecting permit, two large roots in bags soon were
loaded on top of the bus to Orizaba. When Marker got there, the bags were gone, but he
recovered the larger 50-pound root by bribing a local policeman.

Back at Penn State, Marker isolated diosgenin in satisfactory yield from part of the
smuggled tuber. Because his research had been funded by Parke-Davis, Marker took the
rest of his root to its laboratories in Detroit. There, he repeated his process in an attempt
to persuade the company to commercialize it. However, Parke-Davis's president
refused, because he believed chemical work could not be done in Mexico. Marker's
efforts to interest other pharmaceutical houses also failed, and, by the fall of 1942, he
was convinced the only path to success "was for me to do it myself."

Marker returned to Veracruz and arranged with Moreno to collect and dry about 10 tons
of cabeza de negro. In Mexico City, he found a man with a small-scale extractor, who
extracted the roots with alcohol and evaporated the extract to a syrup. Next, in return for
a third of the product, Marker arranged with a New York friend, Norman Applezweig,
to use his laboratory to convert the syrup to progesterone. Marker finished with three
kilos valued at $80 per gram, then the largest lot of progesterone ever produced.

Founding Mexicos Steroid Hormone Industry

Marker tried to interest Mexican entrepreneurs in exploiting his process. Eventually,

while looking through the Mexico City telephone directory, he saw a listing for
"Laboratorios Hormona, S.A.," a company set up in 1933 by Emeric Somlo and
Federico Lehmann, primarily to produce gland extracts. When contacted, Lehmann
recognized Marker's name, and because of his background in endocrinology, Lehmann
also realized the significance of Marker's proposal. When Somlo arrived, the three
agreed to form a company for the production of steroid hormones.

Marker ended his research program at Penn State during 1943 and resigned on
December 1. He also told Parke-Davis he would only sign patent applications until that
date. When the company delayed until April 1944, Marker refused to assign patent
rights to anyone, including himself, thus granting free use of his invention to anyone
interested. In early 1944, the new Mexican company was chartered and named Syntex,
S.A. (from Synthesis and Mexico). According to Marker, Somlo was to receive 52% of
the shares, Lehmann, 8%, and Marker, 40%, partly in return for his two kilos of
progesterone. Working with four unskilled assistants in space provided by Hormona,
Marker prepared his first kilo of progesterone by March. Within a year, Syntex was
selling progesterone for $50 a gram.

In May 1945, a rancorous dispute between Marker and his partners over profits and
their distribution caused Marker to sever all ties with Syntex and leave the company.
Syntex was unable to make more progesterone because Marker not only had done the
key operations himself but had coded the reagent bottles and left no directions.

By July, Marker was making progesterone in Texcoco, near Mexico City. His new
company, Botanica-mex, was backed financially by Applezweig. Over the next months,
several kilos of progesterone were synthesized, but production ceased in March 1946
because of the physical harassment of the workers by unidentified outsiders. Botanica-
mex's assets were sold to Gedeon Richter Ltd. With Marker intermittently directing the
work, this company started production in Mexico City under the name Hormonosynth.
During this time, the cabeza de negro was replaced by another yam called barbasco,
which contained five times as much diosgenin. After Marker retired, the company was
reorganized as Diosynth.

After Marker left, Syntex began a frantic search for someone with the knowledge and
expertise needed to get the company back into business. They found George
Rosenkranz, who had studied at the Swiss ETH and was doing pharmaceutical research
in Cuba. After an unusual job interview in which he actually performed a specific
chemical reaction without directions, he was hired. A few months after Rosenkranz
began work in October 1945, Syntex was again selling progesterone.

Rosenkranz extended the chemistry of diosgenin to the production of testosterone and

other steroid hormones (also done by Marker). More importantly, Rosenkranz built a
powerful research program at Syntex. In part, this was done by playing a major role in
the creation of the "Instituto de Qumica," where a collaborative organic chemistry
research degree was established. He also recruited other Ph.D. chemists for Syntex,
including Carl Djerassi and Alejandro Zaffaroni.

Marker with exposed cabeza de negro Russell Marker (center) with members of
root. Photo by Juan Guzmn. Courtesy The his research team (undated). Courtesy The
Pennsylvania State University Archives. Pennsylvania State University Archives.

Cortisone and the "Pill"

One research program led by Djerassi focused on the conversion of diosgenin to

cortisone. Early in 1949, Philip Hench and Edward Kendall at the Mayo Clinic had
reported spectacular results from the treatment of rheumatoid arthritis with cortisone.
Newspapers featured stories of crippled arthritics dancing in the streets after therapy.
The medical community soon recognized the value of cortisone (and cortisol) in the
treatment of other inflammatory conditions, but it was too expensive for widespread
use. At that time, cortisone could only be made by a laborious 36-step Merck & Co.
process that started with desoxycholic acid isolated from ox bile. Syntex completed its
synthesis of cortisone from diosgenin; however, this achievement immediately was
overtaken by another scientific breakthrough.
In 1951, scientists at the Upjohn Co. introduced a microbiological process, which
specifically oxidized progesterone to a product that was easily converted to cortisone.
As Rosenkranz later recalled, "...in July 1951, I received a phone call from Upjohn
asking me whether we would be able to accept an order for 10 tons of progesterone at
48 cents per gram. The going price at the time was in the $2 range and the quantity was
unheard of." Soon, most cortisone was manufactured by Upjohn's process using Syntex
progesterone, although the Merck route was improved enough to remain competitive.

Syntex also competed with other drug companies in the hunt for an effective oral
contraceptive. Because progesterone prevents ovulation during pregnancy, research
focused on the discovery of an orally active progesterone mimic. Using expertise
obtained in the conversion of testosterone to estradiol and estrone, along with two
important leads from the chemical literature, Djerassi's group designed and, in 1951,
synthesized norethindrone, the active ingredient in the first practical oral contraceptive.
For many reasons, the first "pill" to be marketed was G. D. Searle and Co.'s
norethynodrel, but norethindrone accounted for more than half of the oral contraceptive
market in the 1970s.

By the 1950s, Syntex and its competitors in Mexico* were producing more than half the
sex hormones sold in the United States. Syntex's economic success was matched by its
scientific reputation, which was boosted by a very liberal publication policy.
Contributions made by Syntex accounted for more than 30% of all industrial citations in
the Fiesers' definitive 1959 monograph, Steroids. In 1951, Fortune magazine headlined:
"Syntex makes the biggest technological boom ever heard south of the border."
Considering the impact the Mexican steroid industry would have on world health and
culture, Fortune greatly underestimated the power of the explosion.

Russell Marker and Carl Djerassi (undated).

Courtesy The Pennsylvania State University Archives.